title: Efficacy of bevacizumab (Bev) plus chemotherapy (CT) compared to CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC): systematic review and meta-analysis.
abstract: OBJECTIVE
  To perform a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of chemotherapy (CT) plus Bevacizumab (Bev) versus CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The endpoints were overall survival (OS), progression-free survival (PFS) and side effects. We performed a meta-analysis (MA) of the published data, using a fixed effects model and an additional random effects model, when applicable. The results of the MA are expressed as hazard ratio (HR) or risk ratio (RR), with their corresponding 95% confidence intervals (CI95%). We analyzed the use of Bev in the doses of 7.5 mg/kg and 15 mg/kg.
  
  
  RESULTS
  The final analysis included 4 trials, comprising 2200 patients. The response rate was higher in patients who received the combination of CT plus Bev 7.5 mg/kg (RR=0.58; CI95%=0.46-0.74; p<0.00001) and Bev 15 mg/kg (RR=0.53; CI95%=0.45-0.63; p<0.00001) with moderate heterogeneity at dose of 15 mg/kg (Chi(2)=4.30, df=3 (P=0.23); I(2)=30%). The PFS length was longer in patients who received CT plus Bev 7.5 mg/kg (HR=0.78, CI95%=0.68-0.90; p=0.0005) and Bev 15 mg/kg (HR=0.72, CI95%=0.65-0.80; p<0.00001) with moderate heterogeneity (Bev 7.5 mg/kg: Chi(2)=1.43, df=1 (P=0.23); I(2)=30% and Bev 15 mg/kg: Chi(2)=7.43, df=3 (P=0.06); I(2)=60%). Differences in these end points remained in favor of CT plus Bev when made the analysis by random-effects model. Overall survival was longer in patients who received CT plus Bev 15 mg/kg (HR=0.89, CI95%=0.80-1.00; p=0.04), with moderate heterogeneity (Chi(2)=5.09, df=3 (P=0.17); I(2)=41%). The random-effects model analysis for this endpoint did not confirmed the difference seen in the fixed effects model analysis (HR=0.90, CI95%=0.76-1.07; p=0.23). Severe haematologic toxicities (grade>3), neutropenia and febrile neutropenia were more common among the patients that received Bev.
  
  
  CONCLUSIONS
  The combination of CT plus Bev increased the response rate and progression-free survival of patients with NSCLC. With respect to overall survival the benefits of Bev remains uncertain.
authors.affiliation: Evidencias Consulting, Rua Tranquillo Prosperi, 143, Campinas, São Paulo ZIP: 13084-778, Brazil.
authors.forename: Tobias Engel Ayer
authors.initials: TE
authors.lastname: Botrel
authors.forename: Otávio
authors.initials: O
authors.lastname: Clark
authors.forename: Luciana
authors.initials: L
authors.lastname: Clark
authors.forename: Luciano
authors.initials: L
authors.lastname: Paladini
authors.forename: Enéas
authors.initials: E
authors.lastname: Faleiros
authors.forename: Bruna
authors.initials: B
authors.lastname: Pegoretti
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D054796:Drug Dosage Calculations; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009503:Neutropenia / Q000209:etiology; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab